The goal of the proposed research program is to use antisense, transgenic technologies to develop a murine hepatitis virus (MHV)- resistant strain of mice. During Phase I we will: 1) test the antiviral efficacy, in tissue culture, of antisense oligonucleotides complementary to specific regions of the MHV genome; and 2) develop plasmin constructs containing similar sequences and produce transformants that express those sequences as antisense RNAs. These transformants will then be tested for their susceptibility and resistance to infection by MHV. The findings of these studies will be applied in Phase II to the development of the proper strategy for developing hepatitis- resistant strains of mice. This work has major significance in three areas. First, because hepatitis virus is a common contagion in mouse colonies, the development of resistant strains may help to reduce colony loss and colony maintenance costs. Second, the results will also help define the mechanism of action of the two types of antiviral antisense therapies. This study will represent the first comparison of these antiviral strategies on a single system. Third, should our efforts be successful in producing MHV-resistant mice, similar procedures for control of coronavirus infection in other animals (cattle, pigs and poultry) can be explored.